1999 Fiscal Year Final Research Report Summary
Relationship between intracellular traffic of proteins containing expanded polyglutamine, aggregate formation, and cell death
| Project/Area Number |
10470156
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | International University of Health and Welfare (1999)
Jichi Medical University (1998) |
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Principal Investigator |
NISHIZAWA Masatoyo International University of Health and Welfare, Department of Health Science, Professor, 保健学部, 教授 (80198457)
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| Co-Investigator(Kenkyū-buntansha) |
TAKIYAMA Yoshihisa Jichi Medical School, Department of Neurology, Instructor, 保健学部, 講師 (00245052)
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| Project Period (FY) |
1998 – 1999
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| Keywords | CAG repeat / polyglutamine / aggregate formation / neuronal cell death / microtubulus organizing center |
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| Research Abstract |
In order to elucidate the mechanism of selective neuronal cell death in polyglutamine diseases caused by abnormal expansion of CAG repeat units, various constructs expressing part of ataxin-3, the product of the disease-causing gene MJD 1 of Machado-Joseph disease, as fusion protein with GFP, were introduced to COS cells, and subcellular localization of expressed ataxin-3 fragments was analyzed under fluorescence microscopy.
We found that the C-terminal end of ataxin-3 is essential to formation of cytoplasmic aggregates. These cytoplasmic aggregates were surrounding the nucleus and formed mostly in the juxtanuclear region. Confocal laser microscopy revealed that these aggregates were co-localized with tubulin, and especially, juxtanuclear aggregates were co-localized with gamma-tubulin, which is now known as a marker of microtubulus organizing center (MTOC). These results indicate that the C-terminal portion of ataxin-3 can interact with tubulins, and the aggregates formed by expanded polyglutamine and the C-terminal region, accumulate in the MTOCs.
The N-terminal region flanking the polyglutamine tract of ataxin-3 contained active sequence of nuclear localization signal and also a region with coiled-coil conformation. The latter region was found to be invloved in the aggregates formed by expanded polyglutamine. Overexpression of the construct expressing the latter region resulted in the reduction of intranuclear aggregates formed by expanded polyglutamine derived from DRPLA protein and subsequent cell death.
Our present study indicates the important role of intramolecular domains of the products of disease-causig genes in the formation of cytoplasmic and intranuclear aggregates.
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[Publications] Takiyama Y, Shimazaki H, Morita M, Soutome M, Sakoe K, Esumi E, Yoshida M, Igarashi S, Tanaka H, Tsuji S, Sasaki H, Wakisaka A, Nakano I, Nishizawa M: "Maternal anticipation in Machado-Joseph disease (MJD): some familial factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family."J Neurol Sci. 155. 141-145 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Takano H, Cancel 0, Ikeuchi T, Lorenzetti D, Mawad R, Stevanin 0, Didierjean 0, Durr A, Oyake M, Shimohata T, Sasaki R, Koide R, Igarashi S, Hayashi S, Takiyama Y, Nishizawa M, Tanaka H, Zoghbi H, Brice A, Tsuji S: "Close associations between the prevalence rates of dominantly inherited spinocerebellar ataxias with CAG repeat expansions and the frequencies of large normal CAG alleles in Japanese and Caucasian populations."Am I Hum Genet. 63. 1060-1066 (1998)
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「研究成果報告書概要(欧文)」より
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